NEW
YORK, Aug. 8, 2024 /PRNewswire/ -- An activity
pattern in certain genes responsible for building proteins known as
spleen tyrosine kinases can predict which melanoma patients are
likely to have severe side effects from immunotherapy designed to
treat the most deadly skin cancer, a new study shows.
Led by researchers at NYU Langone Health and its Perlmutter
Cancer Center, the latest experiments focused on checkpoint
inhibitors, drugs that have in the last decade become a mainstay of
treating melanoma. This form of skin cancer kills nearly 10,000
Americans annually.
The drugs work by blocking molecules (checkpoints) that sit on
the surface of immune T cells and stop them from attacking cancer
cells like they would invading viruses or bacteria. While the
immune system normally uses checkpoints to recognize and protect
healthy cells, cancer cells are able to hijack and turn off immune
cell surveillance, evading detection. Immunotherapy drugs like
nivolumab and ipilimumab are designed to block checkpoints, making
cancer cells more "visible" again to T cells.
However, more than a third of melanoma patients given checkpoint
inhibitors develop side effects so severe that they compromise
their quality of life and ability to continue therapy. Side effects
most often involve some form of inflammation, a sign of an
overactive immune response. Patients can experience severe skin
rashes, diarrhea, or hyperthyroidism. More severe side effects can
include liver toxicity, colitis, and rheumatoid arthritis.
In the new study, publishing in the journal Clinical Cancer
Research online Aug. 8,
researchers found that even before treatment began in their test
subjects, the activity of genes controlling the production of
spleen tyrosine kinases predicted 83 percent of melanoma patients
who eventually developed severe side effects from combined
immunotherapy with nivolumab and ipilimumab.
Moreover, the researchers found that this heightened gene
signature, as evidenced by the production of spleen tyrosine
kinases, or the SYK pathway, did not interfere with the
effectiveness of therapies in preventing recurrence of melanoma.
The impact was connected only to side effects.
"Our study results show that increased gene activity in the
spleen tyrosine kinase pathway could be the basis of a possible
blood test that identifies melanoma patients most susceptible to
having severe side effects from immunotherapy, and well before they
start treatment," said study co-senior investigator Tomas Kirchhoff, PhD. Kirchhoff is an associate
professor in the Department of Population Health at NYU Grossman
School of Medicine and a member of Perlmutter Cancer Center.
"Predictive information of this kind is critically important to
oncologists and patients to help guide their immunotherapy
decisions, to either minimize these side effects by taking
additional precautions or choose alternative immunotherapies," said
study co-lead investigator Kelsey
Monson, PhD.
For the study, researchers analyzed immune system cell samples
from 212 men and women with melanoma participating in a national
multicenter trial called CheckMate-915. The trial was designed to
test whether combined therapy with nivolumab and ipilimumab worked
better than single therapy with nivolumab in preventing
postsurgical recurrence of melanoma. All immune cell samples were
taken prior to the start of immunotherapy. Both drugs are
manufactured by the pharmaceutical company Bristol Myers Squibb,
which sponsored the CheckMate-915 trial, and provided the patient
specimens and data used in the analysis.
When researchers looked at what genes were more active than
others in patients who experienced side effects from their
immunotherapy, they found a specific pattern among 24 genes tied to
the production of spleen tyrosine kinases. Further statistical
analyses showed that increased or decreased activity
(transcription) of only five of these genes — CD22, PAG1, CD33,
HNRNPU, and FCGR2C — along with age and stage severity of their
melanoma served as the best predictors of who would experience
immunotherapy side effects.
Study co-senior investigator Jeffrey
Weber, MD, PhD, says that the SYK pathway has previously
been linked to other autoimmune diseases, including lupus,
rheumatoid arthritis, and colitis, disorders marked by immune
system attack on healthy cells. He also points out that
immunotherapy side effects were also most common in areas affected
by these autoimmune diseases, including the skin, colon, and
liver.
Weber, the Laura and Isaac Perlmutter Professor of Oncology in
the Department of Medicine at NYU Grossman School of Medicine, says
the team next plans to investigate if an activated SYK pathway is
predictive of side effects in patients treated with ipilimumab
alone or with other combination immunotherapies. Weber also serves
as deputy director of NYU Langone's Perlmutter Cancer Center.
"If our future research can explain how an activated spleen
tyrosine kinase pathway leads to increased risk of side effects
from immunotherapy, then it could also potentially help us to
design better cancer immunotherapies and potentially other
treatments for autoimmune diseases," said Kirchhoff.
Funding for the study was provided by National Institutes of
Health grants P50CA225450, F99CA274650, and R01CA227505, with
additional support from Melanoma Research Alliance grant
MRA-686192.
Weber owns equity in Altor BioScience, Biond Biologics, and
CytomX Therapeutics. He has also received honoraria from Bristol
Myers Squibb, Merck, Genentech, AbbVie, AstraZeneca, Daiichi
Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Amgen, Roche,
Ichor Medical Systems, Celldex Therapeutics, CytomX Theraputics,
Nektar, Novartis, SELLAS, WindMIL Therapeutics, and Takeda. Weber
has been a paid consultant or advisor to Celldex, Ichor Medical
Systems, Biond Biologics, Altor BioScience, Bristol Myers Squibb,
Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline,
Daiichi Sankyo, AbbVie, Eisai, CytomX Therapeutics, Nektar,
Novartis, SELLAS, WindMIL Therapeutics, and Takeda. He has also
received research funding from Bristol Myers Squibb,
GlaxoSmithKline, Daiichi Sankyo, Roche, Celldex Therapeutics,
Amgen, Merck, AstraZeneca, Genentech, Novartis, WindMIIL
Therapeutics, and Takeda. All of these arrangements are being
managed in accordance with the policies and practices of NYU
Langone Health.
Besides Kirchhoff and Weber, other NYU Langone researchers
involved in this study are co-lead investigator Robert Ferguson, and co-investigators
Joanna Handzlik, Jiahan Xiong, Sasha
Dagayev, Leah Morales, Vylyny Chat,
Anabelle Bunis, Chaitra
Sreenivasaiah, Yongzhao Shao, and Iman
Osman. Other study co-investigators are Sonia Dolfi and Daniel
Tenney at Bristol Myers Squibb in Princeton, NJ.
Media Inquiries:
David March
212-404-3528
David.March@nyulangone.org
STUDY DOI:
http://dx.doi.org/10.1158/1078-0432.CCR-24-0900
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SOURCE NYU Langone Health System